Prostate cancer is over-diagnosed and over-treated, challenging the current standard screening practice: transrectal ultrasound (TRUS) guided random biopsy following blood screening for prostate specific antigen (PSA) [1-2]. TRUS lacks reliable imaging characteristics that differentiate between benign and malignant prostate tissue. Its role is currently restricted to guide random needle biopsies and estimate prostate volume [3]. In May 2012, the United States Preventive Services Task Force (USPSTF) recommended against routine PSA screening, with the rationale that too many non-lethal cancers were being treated aggressively and that the potential benefits do not outweigh the harms. Despite these recommendations, there are prostate cancers that can behave aggressively, and metastasize and kill men, evidenced by prostate cancer's position as the second leading cause of male cancer death in the US. Imaging could change prostate cancer care by allowing for more accurate biopsies by showing the target tumor so that grade is better assessed and allowing clinicians to estimate tumor volume. Therefore any imaging strategy that allows delineation for the tumors in the prostate would be a major step forward in estimating the aggressiveness of prostate cancer. Imaging could therefore improve care by improving confidence in selecting men for active surveillance, surgery or radiation therapy. In addition, accurate delineation of the tumor within the prostate could open avenues for new approaches to the management of localized prostate cancer such as focal therapy, as well as allowing monitoring of response to therapies Recent study on histopathology specimens of a large cohort of patients demonstrated that prostate tumors are angiogenic, and aggressive tumors tend to have blood vessels that are small and irregular in cross-section, while indolent tumors have normal blood vessels [8]. In my postdoctoral research work in the laboratory of Dr. Sanjiv Gambhir, I have demonstrated that photoacoustic imaging (PAI) can reliably image angiogenesis of prostate tumors using prostate cancer mice (PCM) models. Since the main goal of my research is clinical translation, working in the ultrasound laboratory of my co-mentor Dr. B.T. Khuri-Yakub, I have further developed a novel prostate imaging device: a combined real time three dimensional (rt3D) transrectal ultrasound and photoacoustic (TRUSPA) device using home built two dimensional (2D) capacitive micromachined ultrasound transducer (CMUT) arrays. These findings offer promise for novel dual modality imaging strategy that could provide new diagnostic and prognostic insights into prostate cancer screening and treatment. Here, I propose to merge my prior training in optical, ultrasound and biomedical engineering with new training in molecular imaging of cancer to develop a clinical grade rt3D TRUSPA imaging system and further investigate its use as a diagnostic as well as prognostic screening tool. In Aim 1 (K99 phase), with the help of mathematical, computer simulation and design tools, I will optimize and engineer different components of TRUSPA device to reliably image deep into the posterior surface (4 cm to 5 cm from the rectal wall) of human prostate in both ultrasound and PA modes. In Aim 2A (bridging K99/R00 phases), I will systematically investigate vascular (angiogenesis), functional (hypoxia related), metabolic and molecular (targeting molecules highly expressed in prostate cancer) signatures of prostate cancer to establish quantitative imaging metrics that have potential to reliably predict diagnostic and prognostic features of the cancer using dual modality ultrasound and photoacoustic imaging strategies in PCM models. In Aim 2B (R00 phase), I will accomplish a clinical grade rt3D TRUSPA dual modality imaging system by integrating successful imaging strategies of Aims 1 and 2A. While ultrasound mode will provide anatomical/structural information of the prostate including hyper and hyopoechoic regions, PA mode will provide optical contrast of the prostate leveraging on successful vascular, functional and molecular imaging metrics of Aim2A. The hypothesis is that these metrics can reliably image diagnostic and prognostic features of the cancer. These pre-clinical studies will help us further fine tune rt3D TRUPA imaging strategies that has potential to succeed in clinic. This Transition to Independence proposal describes research and career development activities, including conference attendance and course training that will establish me as a competitive candidate for an independent faculty position and aid my development of an innovative, successful multidisciplinary research program in biomedical engineering and cancer molecular imaging with particular focus on elucidating mechanisms of prostate cancer development and its response to therapy. These activities will be mentored by Drs. Sanjiv Gambhir (primary mentor, Molecular Imaging Program at Stanford, Radiology), Butrus. T. Khuri-Yakub (co-mentor, Electrical Engineering Dept., expert in ultrasound imaging and CMUT array design and fabrication), Juergen Willman (co-mentor, Radiology Dept., expert in ultrasound molecular imaging and canine prostate cancer models), James D. Brooks (co-mentor, Urology Dept., expert in clinical prostate cancer management, clinical trials, imaging and biomarker development) and Joseph C. Liao (co-mentor, Urology Dept., urologic surgeon and expert in technology validation) at Stanford University, which is a world-class research institute for engineering and cancer molecular imaging.